Process for the preparation of 1-alkylthio-and 1-benzylthio-1-formylcyclopropanes

ABSTRACT

Compounds of formula I ##STR1## wherein R is C 1  -C 4  alkyl or benzyl, are prepared by reacting a butanal of formula II ##STR2## wherein X and Y are each independently of the other chloro, bromo or iodo, in an inert solvent, with a compound of formula III 
     
         R--S--Me                                                   (III) 
    
     wherein R is as defined above and Me is an alkali metal cation, and converting the resultant compound of formula IV ##STR3## wherein X and R are as defined above, in an inert solvent and in the presence of a base, into a compound of formula I.

The present invention relates to a novel process for the preparation of1-alkylthio- and 1-benzylthio-1-formylcyclopropanes of formula I##STR4## wherein R is C₁ -C₄ alkyl or benzyl.

Alkyl will be understood as meaning linear or branched alkyl. SuitableC₁ -C₄ alkyl radicals are typically methyl, ethyl, n-propyl, isopropyl,n-butyl or the butyl isomers.

The 1-alkylthio- and 1-benzylthio-1-formylcyclopropanes of formula I areuseful intermediates for the synthesis of the herbicidalacylcyclohexanediones disclosed, for example, in European patentapplication No. 0 243 313.

In German Offenlegungsschrift No. 2 120 908 it is taught to prepare1-methylthio-1-formylcyclopropanes by

(a) reacting methylthioacetonitrile, in the presence of sodium amide,with 1,2-dibromoethene to give 1-cyano-1-methylthiocyclopropane offormula V ##STR5##

(b) converting said compound of formula (V) with concentratedhydrochloric acid to the corresponding cyclopropanecarboxylic acid offormula VI ##STR6##

(c) reacting the carboxylic acid of formula VI with thionyl chloride tothe acid chloride of formula VII ##STR7##

(d) reacting the acid chloride so obtained with ethyleneimine andtriethylamine to the amide of formula VIII ##STR8## and, finally,

(e) reacting the amide of formula VIII with lithium aluminium hydride togive the final product, 1-formyl-1-methylthiocyclopropane.

The yields obtainable in this known process are very low. For example,in process step (a) the compound of formula V is obtained only in ayield of 16.8%. Based on the starting methylthioacetronitrile, the yieldof final product in this five-step process is only ca. 4%.

Aside from the unsatisfactory yield for large-scale production, thelarge number of synthesis and working up steps make this process verytime-consuming and cost-intensive.

There has now been found a novel process which makes it possible toprepare 1-alkylthio- and 1-benzylthio-1-formylcyclopropanes inparticularly simple manner and in high yield and good purity.

The process of this invention for the preparation of compounds offormula I ##STR9## wherein R is C₁ -C₄ alkyl or benzyl, comprisesreacting a butanal of formula II ##STR10## wherein X and Y are eachindependently of the other chloro, bromo or iodo, in an inert solvent,with a compound of formula III

    R--S--Me                                                   (III)

wherein R is as defined above and Me is an alkali metal cation, andconverting the resultant compound of formula IV ##STR11## wherein X andR are as defined above, in an inert solvent and in the presence of abase, into a compound of formula I.

Illustrative of suitable solvents for the process of this invention arecompounds or mixtures selected from the group of open-chain and cyclicethers such as dioxane, tetrahydrofuran, diethyl ether, diisopropylether, dimethoxymethane and 1,2-dimethoxyethane, or from the group ofthe alcohols such as methanol, ethanol, propanol, isopropanol andbutanol, or water. Methanol, tetrahydrofuran and water have been foundto be particularly suitable solvents.

As already described above, Me is an alkali metal, and is preferablylithium, sodium or potassium.

Suitable bases are typically oxides, hydroxides, carbonates,carboxylates or alcoholates of an alkali metal or alkaline earth metal.Sodium methylate, sodium hydroxide, potassium hydroxide, sodiumcarbonate or potassium carbonate have been found to be especiallysuitable. The most preferred base is sodium methylate, sodium hydroxideor potassium hydroxide.

The process of this invention can be carried out within a widetemperature range. A temperature range from -10° to +100° C. has beenfound very suitable. A preferred temperature range is from -10° to +50°C.

The thiol salts of formula III may be used direct and also produced insitu. For example, sodium thiomethylate can be produced by passingmethyl mercaptan into an aqueous solution of sodium hydroxide.

The starting compounds of formula II are novel and are likewise anobject of the invention. They can be prepared from the corresponding4-halobutanals by methods analogous to those known in the literature.Examples of such synthesis will be found in the following publications:

J. Org. Chem. (1974), 39, 1785;

Chem. Ber. (1985), 118, 4288;

Synthesis (1978), 140;

J. Org. Chem. (1983), 48, 3493;

Synthesis (1986), 678.

The intermediates of formula IV are novel compounds and constitute afurther object of the invention.

The process of this invention can be carried out with as well as withoutisolation of the intermediates of formula IV.

A preferred variant of the process of this invention comprises reactingthe compound of formula II with the compound of formula III, withoutisolation of the intermediate of formula IV, in an inert solvent and inthe presence of a base, to give the compound of formula I.

Starting materials of formula II which are especially suitable for thesynthesis of the compounds of formula I are those in which X is chloroand Y is chloro or bromo. Particularly suitable compounds of formula IIare those wherein X and Y are chloro.

A particularly preferred variant of the process of this inventioncomprises reacting a compound of formula II, wherein X is chloro and Yis chloro or bromo, direct with sodium thiomethylate, in the temperaturerange from -10° C. to +50° C., and in the presence of aqueous sodiumhydroxide, in a one pot reaction.

The compounds of formula I may be obtained in the procss of thisinvention in particularly simple manner and in high purity and goodyield. The single step or-if isolation of the intermediate of formula IVis desired-two-step mode of carrying out the process eliminates thenumerous time-consuming processing steps of the known process, whichnormally result in losses in yield.

The invention is illustrated by the following non-limitative Examples.

PREPARATORY EXAMPLES EXAMPLE 1 Preparation of 2-bromo-4-chlorobutanal(compound 1.1)

With efficient stirring, 12 ml of a 33% solution of hydrogen bromide inacetic acid are added dropwise to a suspension of 120 g of4-chlorobutanal and 130 g of 5,5-dibromobarbituric acid in 600 ml ofdiethyl ether, the temperature rising to 35° C. upon onset of thereaction. After 3 to 4 hours, the reaction mixture, which has cooled toroom temperature, is filtered. The filtrate is subsequently washed insuccession with a dilute solution of sodium hydrogen carbonate and witha saturated solution of sodium chloride until neutral, and dried oversodium sulfate. The solvent is removed by evaporation at 40° C.,affording 133 g of 2-bromo-4-chlorobutanal in a yield of 70% of theoryand in 93% purity. After purification by distillation at a pressure of1900 Pa, the boiling point is 74°-75° C.

EXAMPLE 2 Preparation of 2,4-dichlorobutanal (compound 1.2)

While cooling with ice, 270 g of sulfuryl chloride are added dropwiseover 75 minutes to a solution of 237 g of 4-chlorobutanal (90%) in 80 mlof dichloromethane. During this addition, the temperature of thereaction mixture is 10°-20° C. The reaction mixture is then kept for 30minutes at 5°-10° C., and subsequently refluxed for 2 hours until theevolution of gas ceases. The reaction product is finally obtained byfractional distillation over a 40 cm packed column at 6000 Pa in a yieldof 221 g. Boiling point: 90° C. Purification by super-fractionation at9000 Pa over a 20 cm packed column gives 194.1 g (54.7% of theory) of2,4-dichlorobutanal in 79.5% purity. Boiling point: 96°-99° C.

EXAMPLE 3 Preparation of 4-chloro-2-iodobutanal (compound 1.3)

1.5 ml of 57% hydriodic acid are added to a suspension of 59.1 g of4-chlorobutanal (90%), 68 g of mercury (II) chloride and 127 g of iodinein 500 ml of dichloromethane, and the reaction mixture is stirred for 24hours under reflux. During this time, hydrogen chloride evolves slowlyfrom the reaction mixture, accompanied by the formation of red mercury(II) iodide. The reaction solution is filtered and the filtrate iswashed twice with sodium thiosulfate solution and once with a solutionof potassium iodide and sodium hydrogen carbonate. After drying overmagnesium sulfate, the filtrate is concentrated by evaporation and theresidue is fractionated over a 30 cm packed column, affording 85.3 g of4-chloro-2-iodobutanal in the form of a yellowish red oil in a yield of61% of theory and a purity of 84%. The boiling point is 46°-47° C./1.3Pa.

EXAMPLE 4 Preparation of 2,4-dibromobutanal (compound 1.4)

With efficient stirring, 1.4 ml of a 33% solution of hydrogen bromide inacetic acid are added dropwise to suspension of 70 g of 4-bromobutanal(98.8%) and 65.6 g of 5,5-dibromobarbituric acid in 300 ml of diethylether. The temperature of the reaction mixture rises over 2 hours to 31°C. After a further 2 hours, the reaction mixture has cooled again toroom temperature. The mixture is cooled to 0° C. and filtered. Thefiltrate is then washed 3 times with a saturated solution of sodiumchloride and a small amount of sodium hydrogen carbonate solution. Thefiltrate is dried over magnesium sulfate and the solution isconcentrated by evaporation, affording 90 g of a pale yellow oil in91.1% purity.

Working up of the crude product by distillation over a Vigreux column at1.3 Pa gives 39.7 g of 2,4-dibromobutanal (34% of theory) in the form ofa colourless, slightly mobile oil in 92% purity. Boiling point: 42°-45°C.

The following compounds of formula II are also obtained in accordancewith the procedure dscribed above:

    ______________________________________                                         ##STR12##                    (II)                                            Compound           X          Y                                               ______________________________________                                        1.5                Br         Cl                                              1.6                Br         J                                               1.7                J          Cl                                              1.8                J          Br                                              1.9                J          J                                               ______________________________________                                    

EXAMPLE 5 Preparation of 4-chloro-2-methylthiobutanal (compound 3.1)

A solution of 26.2 g of sodium thiomethylate in 170 ml of methanol areadded dropwise at a temperature of -5° C. over 20 minutes to 54.8 g offreshly distilled 2,4-dichlorobutanal (96%) in 100 ml oftetrahydrofuran. The reaction mixture is kept for 18 hours at roomtemperature, then diluted with diethyl ether and thereafter extractedwith water. The organic phase is then washed twice with a saturatedsolution of sodium chloride and once with a solution of sodium hydrogencarbonate, dried over magnesium sulfate and concentrated over a columnunder atmospheric pressure. The reaction mixture is then distilled overa 30 cm packed column at 2600 Pa, giving 6.7 g of4-chloro-2-methylthiobutanal (compound 3.1) in the form of a colourlessoil which boils at 104° C./2600 Pa.

EXAMPLE 6 Preparation of 1-formyl-1-methylthiocyclopropane (compound2.1)

15 ml of a 3N aqueous solution of sodium hydroxide are added at 25° C.to 6 g of 4-chloro-2-methylthiobutanal (compound 3.1) in 2 ml ofmethanol. The reaction mixture is stirred for 35 minutes and thenextracted twice with diethyl ether, and the extracts are washed with asaturated solution of sodium chloride. The combined organic phases aredried over magnesium sulfate. The solution is concentrated over a columnunder atmospheric pressure, and the residue is then distilled in a bombtube under atmospheric pressure at 150°-200° C., giving 2.4 g of1-formyl-1-methylthiocyclopropane (compound 2.1) in the form of an oil.

EXAMPLE 7 Preparation of 1-formyl-1-methylthiocyclopropane (compound2.1)

A solution of 58.6 g of 2-bromo-4-chlorobutanal (freshly distilled, 95%)in 50 ml of methanol is prepared while cooling with ice. With cooling,22.4 g of 94% sodium thiomethylate in 130 ml of methanol are then addeddropwise to this solution over 15 minutes. During this addition, thetemperature of the reaction mixture is 20°-23° C. After 15 minutes, 54 gof a 30% solution of sodium methylate in methanol are added dropwiseover 1 to 2 minutes to the 4-chloro-2-methylthiobutanal obtained asintermediate (compound 3.1). During this addition, the temperature ofthe reaction mixture rises to 30° C. After the reaction has subsided,water is added and the mixture is extracted three times with diethylether. The combined organic phases are washed with a saturated solutionof sodium chloride and subsequently dried over magnesium sulfate. Thesolution is concentrated under atmospheric pressure over a column, andthe residue is fractionated over a packed column, affording 23.8 g (67%of theory) of 1-formyl-1-methylthiocyclopropane in 98% purity. Boilingpoint: 88°-91° C. at 9 600 to 10 000 Pa.

EXAMPLE 8 Preparation of 1-formyl-1-methylthiocyclopropane (compound2.1.)

While cooling with ice, 38 g of sodium thiomethylate are added inportions over 30 minutes to a solution of 81 g of 2,4-dichlorobutanal(92%) in 300 ml of tetrahydrofuran, whereupon the intermediate,4-chloro-2-methylthiobutanal, forms (compound 3.1). The reaction mixtureis kept for 24 hours at room temperature and then, with efficientstirring and intensive cooling, 95.4 g of a 30% solution of sodiummethylate in methanol are added at 0° C. over 15 minutes. The reactionmixture is then allowed to warm to room temperature. After extraction byaddition of 250 ml of water and 250 ml of diethyl ether, the aqueousphase is separated and extracted a second time with 250 ml of diethylether. The combined organic phases are subsequently washed with two 250ml portions of saturated sodium chloride solution and dried overmagnesium sulfate. The solution is concentrated under atmosphericpressure over a column. Fractionation of the residue over a 30 cm packedcolumn gives 30.5 g (47% of theory) of 1-formyl-1-methylthiocyclopropanein 97% purity. Boiling point: 92° C. at 10 200-10 400 Pa.

EXAMPLE 9 Preparation of 1-formyl-1-methylthiocyclopropane (compound2.1)

720 g of a 30% solution of sodium methylate in methanol (2 eq.) arediluted with 100 ml of methanol. While cooling with ice/sodium chloride,90 g of methyl mercaptan are passed into this solution at 0°-5° C.,whereupon sodium thiomethylate forms. Then 264 g of freshly distilled2,4-dichlorobutanal are added dropwise over 20 minutes to the reactionsolution, whereupon sodium chloride precipitates immediately and thetemperature of the reaction mixture rises to 37° C. After 90 minutes,the reaction mixture is extracted by addition of 1 liter of water of 1liter of diethyl ether. The organic phase is then separated, and theaqueous phase is extracted with another four 250 ml portions of diethylether. The combined organic phases are washed with a saturated solutionof sodium chloride and dried over magnesium sulfate. The reactionmixture is concentrated under atmospheric pressure over a packed column.Fractional distillation of the residue over a 40 cm packed column gives168 g (75% of theory) of 1-formyl-1-methylthiocyclopropane in 97%purity. Boiling point: 92°-93° C./10 400 Pa.

EXAMPLE 10 Preparation of 1-formyl-1-methylthiocyclopropane (compound2.1 )

With stirring, 120.3 g of sodium thiomethylate (97%) are added to asolution of 107.5 g of pulverised potassium hydroxide (86%) in 600 ml ofmethanol. The clear, yellowish solution is cooled to 15° C., and then asolution of 230 g of 2,4-dichlorobutanal (98%) in 200 ml oftetrahydrofuran is added dropwise over 25 minutes while cooling withice. During this addition, the temperature of the reaction mixture is30°-40° C. After 1 hour, 1 liter of water is added and the reactionmixture is extracted with four 300 ml portions of diethyl ether. Thecombined organic extracts are washed with a saturated solution of sodiumchloride and dried over magnesium sulfate. The reaction solution is thenconcentrated under atmospheric pressure over a packed column. Fractionaldistillation of the residue under reduced pressure over a 40 cm packedcolumn gives 135.8 g of 1-formyl-1-methylthiocyclopropane (71.8% oftheory) in 99% purity. Boiling point: 89°-91° C./9 600 Pa.

EXAMPLE 11 Preparation of 1-formyl-1-methylthiocyclopropane (compound2.1)

While cooling with ice/sodium chloride, 70 g (1 eq.) of methyl mercaptanare passed into a solution of 116.3 g (2 eq.) of sodium hydroxide in 750ml of water. While maintaining the cooling and with efficient stirring,188.6 g of freshly distilled 2,4-dichlorobutanal (97%) are addeddropwise over 100 minutes. During this addition, the temperature of thereaction mixture rises from 2° C. to 8°-9° C. After 1 hour, the reactionmixture is extracted with four 250 ml portions of diethyl ether. Thecombined organic phases are washed with a saturated solution of sodiumchloride until neutral, dried over magnesium sulfate, and the solutionis concentrated under atmospheric pressure over a packed column.Fractional distillation of the residue under reduced pressure over a 40cm packed column gives 126 g of 1-formyl-1-methylthiocyclopropane (85%of theory) in 99% purity. Boiling point: 91°-92° C./10 000 Pa.

EXAMPLE 12 Preparation of 1-formyl-1-tert-butylthiocyclopropane(compound 2.2)

Under an atmosphere of nitrogen and while cooling with ice, 112 ml oftert-butyl mercaptan are added dropwise over 10 minutes to a solution,cooled to 5° C., of 80 g of sodium hydroxide in 750 ml of water. Then 50ml of methanol are added. After 1 hour, 151 g of 2-bromo-4-chlorobutanal(89.5%) are added dropwise over 15 minutes with efficient stirring andcooling, whereupon the temperature of the reaction mixture rises from 5°to 20° C. After 30 minutes, the mixture is extracted 4 times withdiethyl ether. The combined organic phases are washed twice with asaturated solution of sodium chloride and dried over magnesium sulfate.The residue obtained after concentrating the residue on a rotaryevaporator is fractionated over a 30 cm packed column, affording 89 g of1-formyl-1-tert-butylthiocyclopropane in 89% purity. Boiling point:112°-114° C./8 400 Pa.

The following compounds of formula I are also obtained in accordancewith the foregoing procedures:

    ______________________________________                                         ##STR13##                    (I)                                             Compound  R             Boiling point/Pressure                                ______________________________________                                        2.3       C.sub.2 H.sub.5                                                                             +57 to +58° C./1800 Pa                         2.4       C.sub.3 H.sub.7 -n                                                                          +74 to +76° C./2000 Pa                         2.5       C.sub.3 H.sub.7 -i                                                                          +67 to +68° C./2000 Pa                         2.6       C.sub.4 H.sub.9 -n                                                                          2.6                                                   2.7       C.sub.4 H.sub.9 -i                                                                          2.7                                                   2.8       C.sub.4 H.sub.9 -sec.                                                                       2.8                                                   2.9                                                                                      ##STR14##    +90 to +91° C./1.3 Pa                          ______________________________________                                    

The following intermediates of formula IV are also obtained inaccordance with the procedures described in Examples 5, 7 and 8:

    ______________________________________                                         ##STR15##                    (IV)                                            Compound   X      R         Boiling point/Pressure                            ______________________________________                                        3.2        Cl     C.sub.2 H.sub.5                                             3.3        Cl     C.sub.3 H.sub.7 (n)                                         3.4        Cl     C.sub.3 H.sub.7 (iso)                                       3.5        Cl     C.sub.4 H.sub.9 (n)                                         3.6        Cl     C.sub.4 H.sub.9 (sec.)                                      3.7        Cl     C.sub.4 H.sub.9 (tert.)                                     3.8        Cl     C.sub.4 H.sub.9 (iso)                                       3.9        Br     CH.sub.3                                                    3.10       Br     C.sub.2 H.sub.5                                             3.11       Br     C.sub.3 H.sub.7 (n)                                         3.12       Br     C.sub.3 H.sub.7 (iso)                                       3.13       Br     C.sub.4 H.sub.9 (n)                                         3.14       Br     C.sub.4 H.sub.9 (sec.)                                      3.15       Br     (C.sub.4 H.sub.9 (iso)                                      3.16       Br     C.sub.4 H.sub.9 (tert.)                                     3.17       I      CH.sub.3                                                    3.18       I      C.sub.2 H.sub.5                                             3.19       I      C.sub.3 H.sub.7 (n)                                         3.20       I      C.sub.3 H.sub.7 (iso)                                       3.21       I      C.sub.4 H.sub.9 (n)                                         3.22       I      C.sub.4 H.sub.9 (sec.)                                      3.23       I      (C.sub.4 H.sub.9 (iso)                                      3.24       I      C.sub.4 H.sub.9 (tert.)                                     ______________________________________                                    

What is claimed is:
 1. A process for the preparation of a compound of formula I ##STR16## wherein R is C₁ -C₄ alkyl or benzyl, which comprises reacting a butanal of formula II ##STR17## wherein X and Y are each independently of the other chloro, bromo or iodo, in an inert solvent, with a compound of formula III

    R--S--Me                                                   (III)

wherein R is as defined above and Me is an alkali metal cation, and converting the resultant compound of formula IV ##STR18## wherein X and R are as defined above, in an inert solvent and in the presence of a base, into a compound of formula I.
 2. A process according to claim 1, which comprises reacting the compound of formula II, wherein X and Y are as defined in claim 1, with a compound of formula III, wherein R and Me are as defined in claim 1, without isolation of the intermediate of formula IV, in an inert solvent and in the presence of a base, to give the compound of formula I.
 3. A process according to claim 1 which is carried out in the temperature range from -10° to +100° C.
 4. A process according to claim 1 which is carried out in the temperature range from -10° to +50° C.
 5. A process according to claim 1, wherein the inert solvent is a C₁ -C₄ alcohol, water, tetrahydrofuran or dioxane.
 6. A process according to claim 1, wherein the solvent is methanol, tetrahydrofuran or water.
 7. A process according to claim 1, wherein the base is an oxide, hydroxide, carboxylate, carbonate or alcoholate of an alkali metal or alkine earth metal.
 8. A process according to claim 1, wherein the base is sodium methylate, sodium hydroxide or potassium hydroxide.
 9. A process according to claim 1, wherein R is C₁ -C₄ alkyl.
 10. A process according to claim 1, wherein Me is sodium or potassium.
 11. A process according to claim 1, wherein X is chloro and Y is chloro or bromo.
 12. A process according to claim 1, wherein X and Y are chloro.
 13. A process according to claim 2 which is carried out in the temperature range from -10° to +50° C., in the presence of sodium hydroxide or potassium hydroxide, in water or methanol.
 14. A process according to claim 13, wherein Me is sodium, X is chloro, Y is chloro or bromo, and R is C₁ -C₄ alkyl. 